Ebolaviruses and the closely related Marburgviruses continue to pose a lethal threat to human populations worldwide, especially given their potential use as bioweapons and the lack of effective vaccines or antiviral drugs to combat their pathogenicity and spread. The long-term goal of this proposal is to improve understanding of the extreme pathogenicity of Ebolaviruses by focusing on mechanisms that likely contribute to the classification of this virus as a "Category A Priority" pathogen. Studies in this proposal assess the significance of the secreted glycoprotein (sGP);editing of the sGP mRNA causes a reading frame shift, resulting in expression of the GP receptor-binding/fusion protein. Our preliminary data suggest that sGP expression and sGP mRNA editing have important roles in Ebolavirus pathogenicity, most likely by promoting efficient viral replication via suppression of host antiviral responses. This hypothesis will be tested by characterizing Ebolavirus sGP mutants generated with reverse genetics and by studying their function in vitro. By advancing knowledge of likely determinants of Ebolavirus pathogenicity, we expect to provide compelling new rationales for vaccine and targeted drug development.